The pathology and biology of experimentally induced and naturally occurring neoplasms of rodents are characterized and compared using serial sacrifice studies, immunocytochemistry, automated image analysis with stereology, conventional light microscopy, ultrastructure and histochemistry. Detailed histogenesis investigations were performed for mouse, rat, hamster and monkey liver, rat thyroid gland, mouse and rat lung, and rat pituitary gland. Hepatocellular carcinomas were found to originate in all species from initial focal proliferative hepatocellular lesions. Antibodies to surfactant apoprotein and Clara cell antigens allowed us to show that the vast majority of naturally occurring pulmonary tumors of rats and mice, and tumors induced by N-nitrosodiethylamine and N-nitrosoethylurea in mice and N-nitrosomethylurea in rats were of alveolar type II cell origin; no tumors of Clara cell origin were found. The avidin-biotin peroxidase complex (ABC) immunocytochemical technique was further developed for use in laboratory animals. Seventy-nine different antisera, including several monoclonal antibodies, were used to localize in tissue sections a variety of antigens including cell surface glycoporteins, oncogene-associated protein products, hormones, viruses, fetal antigens, enzymes and lysosomal proteins of large granular lymphocytes (LGL; natural killer cells). The latter has provided a diagnostic tool for LGL leukemia and a powerful method for studying disease processes that involve LGL. A new papovavirus was found in athymic nude rats. The virus caused a wasting disease characterized by salivary gland infection and pneumonia with intranuclear inclusion bodies. The disease was diagnosed by the localization of group-specific antigens in lesions with the use of the ABC immunocytochemical technique. Although no tumors were associated with viral infection, others have reported naturally occurring salivary gland tumors in nude rats. Infected material was given to three investigators for virus isolation, which has been unsuccessful to date.